Designing long-lived peptides for more powerful medicines

"Peptides are potentially powerful components of medicines, because they're just fragments of our natural proteins that our bodies can recognize," said University of Virginia assistant professor of chemical engineering Rachel Letteri. "But one limitation is that they tend to break down quickly, so we need to figure out how to make them more stable."

Letteri's lab, led by her Ph.D. advisee Vincent Gray, has demonstrated an approach for overcoming the longevity problem by designing mirror images of natural peptides called coiled coils.

Coiled coils, helix-shaped peptides resembling curly ribbons twisted together, are found in nearly 10% of the proteins in many organisms. They play critical roles in preparing proteins to properly carry out their jobs, in part by pulling together multiple copies of proteins.

"This happens when individual helices in a protein recognize their match and bind in a specific way, forming the coiled coil," Letteri said. "It's like puzzle pieces fitting together. This binding is crucial for proteins to work as they should."

The binding and connecting features of coiled coils make them especially tantalizing as components for medicines, including biomaterials for tissue regeneration. Yet, like other natural peptides, they degrade quickly.

Previous research has shown that blending natural peptides with their mirror images results in excellent binding and stability. Gray and Letteri wondered if the strategy would also work with coiled coils. Could the team design mirrored coiled coils, with all their medicinal promise, to improve both their specific binding ability and longevity for medicinal use?

Image source: Gray et al.(2024), Biomacromolecules.